1. Field of Invention
The present invention relates to novel pharmaceutical compositions suitable for oral administration to monogastric animals consisting of gelatin capsules containing therein mixtures comprising microencapsulated potassium salt (microcapsules) and hydrophilic surfactant external to the microcapsules and methods of using same. The compositions provide safe and effective, controlled release potassium dosage forms for treating potassium deficiency or prevention of potassium depletion in humans. The inclusion of the surfactant greatly reduces the likelihood for development of local toxicity and severe damage to mucosa in a host having a partial obstruction in the alimentary canal. The microcapsules are non-enteric coated and in mixture with the surfactant are free-flowing when wetted in a restricted space.
2. Description of the Prior Art
Potassium chloride is the salt most frequently employed in order to offset potassium depletion in humans or when the action of the potassium cation is desired. It is used when hypokalemia or hypochloremic alkalosis exists, such as after prolonged diarrhea or vomiting or consequent to adrenal steroid therapy or treatment with certain diuretics, such as the thiazides. It is used to elevate normal plasma potassium levels, such as in the treatment of digitalis intoxication. It may be used as a diuretic.
Potassium chloride is a known irritant to the gastrointestinal tract and administration of the salt may cause nausea, vomiting, epigastric distress, abdominal discomfort and diarrhea. Excessive dosages may cause weakness, listlessness, mental confusion, hypotension, vertigo, heart block and even death. Potassium chloride frequently shows signs of toxicity when administered to humans and must be administered cautiously.
For therapeutic purposes, dosages of potassium chloride of 1 to 2 grams taken 2 to 6 times per day are frequently administered. Various dosage forms of potassium chloride, such as liquids, uncoated and enteric-coated tablets, microcapsules, and the like, have been used in the administration to humans but frequently have been found to cause gastrointestinal ulcers, obstruction, hemorrhage and perforation as well as the symptoms of toxicity previously mentioned due to large concentration of the potassium cation in the system.
Sugar-coated tablets containing potassium chloride in a wax matrix (non-enteric-coated) are marketed as a slowly available potassium source. Physicians Desk Reference (1979), page 794, states "fewer bowel lesions are observed with wax-matrix tablets compared to enteric-coated potassium chloride products, but that there have been reports of upper gastrointestinal bleeding associated with the wax-matrix tablets. Use of these wax-coated products should be discontinued immediately and the possibility of bowel obstruction or perforation considered if severe vomiting, abdominal pain, distention or gastrointestinal bleeding occurs."
The administration of gelatin capsules containing microcapsules having ethyl cellulose as a wall material and potassium chloride as a core material was thought to provide an effective method of supplying potassium cations to humans with a minimum of side effects as compared with other dosage forms. However, it was found that the microencapsulated potassium chloride becomes immobilized during breakdown of the gelatin capsule container and will agglomerate in the alimentary canal. This agglomerate can potentially remain in one location of the alimentary tract, particularly in a partially obstructed narrow passage, and cause damage to the mucosa, such as ulceration and even perforation. In rare cases, stenotic and/or ulcerative lesions may develop due to high concentrations of potassium leaching from immobilized microcapsule agglomerates such as in a partially obstructed duodenum.
Others have used surfactants to improve dissolution rate of drugs when powders agglomerate and teach the rate of dissolution is proportional to the reduction in surface tension of the gastric juice (Remington's Pharmaceutical Sciences, 15th Ed. (1973) p. 297). Others have used surfactants such as Polysorbate 20 as an ingredient interior to microcapsules during preparation of microcapsules and have discussed the adverse effect of such agents on the increased release rate of solids from the microcapsules (Luzzi et al. J. Pharm. Sci. 56 (9), 1174-7 (1967)
Prior to our invention it was not known to combine microencapsulates of potassium salt and hydrophilic surfactant exterior to the microencapsulates in a gelatin capsule to provide a source of controlled release potassium to monogastric animals, relatively free of discomforting side effects in the stomach and free of serious side effects in that small segment of the population who may or may not know they have partial obstruction in the alimentary canal such as in the esophagus or duodenum. Furthermore, it was not known that such combinations would not result in more serious local or general toxic condition in either the stomach or intestines rather than improvement, as it was not known what effect surfactant would have on the interchange of the somewhat toxic potassium ion with the gastric tissue during the absorption process.
The present invention is therefore based on the discovery that mixing hydrophilic surfactant with postassium chloride microcapsules and administered in a capsule will eliminate severe toxicity otherwise caused by the microencapsulated potassium chloride in narrow, partially obstructed passages in the alimentary canal such as the duodenum, while at the same time leaving the rate of potassium chloride release substantially unchanged within a suitable range and creating no new toxicity problems anywhere in the alimentary canal due to mucous barrier upset and exposure to potassium chloride in the presence of surfactant.